Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome.

BACKGROUND & AIMS: African Americans (AAs) have the highest incidence of and mortality resulting from colorectal cancer (CRC) in the United States. Few data are available on genetic and nongenetic risk factors for CRC among AAs. Little is known about cancer risks and mutations in mismatch repair (MMR) genes in AAs with the most common inherited CRC condition, Lynch syndrome. We aimed to characterize phenotype, mutation spectrum, and risk of CRC in AAs with Lynch syndrome. METHODS: We performed a retrospective study of AAs with mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) using databases from 13 US referral centers. We analyzed data on personal and family histories of cancer. Modified segregation analysis conditioned on ascertainment criteria was used to estimate age- and sex-specific CRC cumulative risk, studying members of the mutation-carrying families. RESULTS: We identified 51 AA families with deleterious mutations that disrupt function of the MMR gene product: 31 in MLH1 (61%), 11 in MSH2 (21%), 3 in MSH6 (6%), and 6 in PMS2 (12%); 8 mutations were detected in more than 1 individual, and 11 have not been previously reported. In the 920 members of the 51 families with deleterious mutations, the cumulative risks of CRC at 80 years of age were estimated to be 36.2% (95% confidence interval [CI], 10.5%-83.9%) for men and 29.7% (95% CI, 8.31%-76.1%) for women. CRC risk was significantly higher among individuals with mutations in MLH1 or MSH2 (hazard ratio, 13.9; 95% CI, 3.44-56.5). CONCLUSIONS: We estimate the cumulative risk for CRC in AAs with MMR gene mutations to be similar to that of individuals of European descent with Lynch syndrome. Two-thirds of mutations were found in MLH1, some of which were found in multiple individuals and some that have not been previously reported. Differences in mutation spectrum are likely to reflect the genetic diversity of this population.

Restoration of spermatogenesis in dibromochloropropane (DBCP)-treated rats by hormone suppression.

The exposure of men to the nematocide dibromochloropropane (DBCP) has caused prolonged oligo- and azoospermia, which occasionally reverses spontaneously. We recently demonstrated that in testes of rats treated with a dose of DBCP sufficient to reduce the percentage of tubules producing differentiating germ cells (tubule differentiation index, TDI) to 20%, the tubules lacking differentiating cells contained type A spermatogonia. To determine whether these type A spermatogonia could be stimulated to differentiate, as had been demonstrated previously in other models of toxicant-induced sterility, we suppressed intratesticular testosterone and serum follicle stimulating hormone (FSH) levels with the GnRH agonist Lupron (leuprolide). When the GnRH agonist was given for 10 weeks starting immediately after DBCP exposure, the TDI was maintained at 94%. Even when GnRH-agonist treatment was stopped at week 10, the TDI remained between 65 and 80% 10 weeks later. Late spermatid counts averaged 10 x 10(6) per testis for the GnRH-agonist-treated rats at week 20 compared with 1.7 x 10(6) per testis in rats treated with only DBCP. To determine whether spermatogonial differentiation could be stimulated after the TDI had declined to below 30%, we initiated GnRH-agonist treatment 6 weeks after DBCP exposure. The GnRH treatment increased the TDI to 53% at week 16. These results indicate that, if the same principles apply to humans, suppression of testosterone may be applied to restore spermatogenesis in men rendered azoospermic by DBCP or other reproductive toxicants.

Dibromochloropropane inhibits spermatogonial development in rats.

Exposure to the nematocide dibromochloropropane (DBCP) has caused prolonged oligo- and azoospermia in men. There are questions regarding the cellular targets resulting in this effect. In this study we characterized an animal model, in which four daily injections of DBCP produced prolonged oligospermia in LBNF(1) rats without any indication of recovery. Between 6 and 20 weeks after DBCP treatment, 70% of seminiferous tubules showed an epithelium with Sertoli cells but no differentiating germ cells. About 20% of tubules contained differentiating germ cells and 10% showed occlusion or major morphologic alterations to Sertoli cells. Since gonadotropin levels and intratesticular testosterone (ITT) concentrations were elevated in the DBCP-treated rats, the failure of spermatogonial development could not have been a result of lack of these hormones. The tubules without differentiating germ cells contained actively proliferating and dividing type A spermatogonia, which underwent apoptosis instead of differentiation. Thus, the target for the damaging effect appears not to be the killing of stem spermatogonia, but the loss of their ability to undergo differentiation. The presence of type A spermatogonia in the atrophic tubules indicates the potential for intervention to restore spermatogenesis.

Estrogen enhances recovery from radiation-induced spermatogonial arrest in rat testes.

Irradiation of LBNF(1) rat testes induces spermatogonial differentiation arrest, which can be reversed by gonadotropin-releasing hormone (GnRH) antagonist-induced suppression of intratesticular testosterone (ITT) and follicle-stimulating hormone (FSH). Although exogenous estrogen treatment also enhanced spermatogenic recovery, as measured by the tubule differentiation index (TDI), it was not clear whether estrogen stimulated spermatogonial differentiation only by further suppressing ITT or by an additional independent mechanism as well. To resolve this question, we performed the following experiments. At 15 weeks after irradiation, rats were treated with GnRH antagonist; some also received 17beta-estradiol (E2) and were killed 4 weeks later. GnRH antagonist treatment increased the TDI from 0% to 8%, and addition of E2 further increased the TDI to 39%. However, E2 addition further reduced ITT from 7 ng/g testis, observed with GnRH antagonist to 3 ng/g testis, so decreased ITT levels might have contributed to recovery. Next GnRH antagonist-treated rats were given exogenous testosterone and flutamide to stabilize ITT levels and block its action. This increased TDI slightly from 8% to 13%, but the further addition of E2 significantly raised the TDI to 27%, indicating it acted by a mechanism independent of ITT levels. Plots of TDI for all treatment groups compared with ITT, FSH, or a linear combination of ITT and FSH showed that treatments including E2 produced higher TDI values than did treatments without E2. These results indicate that there was an effect of E2 on spermatogonial differentiation because of an additional direct action on the testis that is unrelated to its suppression of testosterone or gonadotropins.